Hemodynamic and Clinical Outcomes in Redo-Surgical Aortic Valve Replacement vs. Transcatheter Valve-in-Valve

Background Transcatheter valve-in-valve replacement (ViV-TAVR) has emerged as an alternative to redo-surgical aortic valve replacement (Redo-SAVR) for the treatment of failed surgical aortic bioprostheses. However, the benefit of ViV-TAVR compared with Redo-SAVR remains debated with regard to short-term hemodynamic results and short- and long-term clinical outcomes. Objective This study aimed to compare short-term hemodynamic performance and long-term clinical outcomes of ViV-TAVR vs. Redo-SAVR in patients treated for surgical aortic bioprosthetic valve failure. Methods We retrospectively analyzed the data prospectively collected in 184 patients who underwent Redo-SAVR or ViV-TAVR. Transthoracic echocardiography was performed before and after the procedure and analyzed in an echocardiography core laboratory using the new Valve Academic Research Consortium-3 criteria. An inverse probability of treatment weighting was used to compare the outcomes between both procedures. Results ViV-TAVR showed lower rate of intended hemodynamic performance (39.2% vs. 67.7%, p < 0.001) at 30 days, which was essentially driven by a higher rate (56.2% vs. 28.8%, p = 0.001) of high residual gradient (mean transvalvular gradient ≥20 mm Hg). Despite a trend for higher 30-day mortality in the Redo-SAVR vs. ViV-TAVR group (8.7% vs. 2.5%, odds ratio [95% CI]: 3.70 [0.77-17.6]; p = 0.10), the long-term mortality was significantly lower (24.2% vs. 50.1% at 8 years; hazard ratio [95% CI]: 0.48 [0.26-0.91]; p = 0.03) in the Redo-SAVR group. After inverse probability of treatment weighting analysis, Redo-SAVR remained significantly associated with reduced long-term mortality compared with ViV-TAVR (hazard ratio [95% CI]: 0.32 [0.22-0.46]; p < 0.001). Conclusions ViV-TAVR was associated with a lower rate of intended hemodynamic performance and numerically lower mortality at 30 days but higher rates of long-term mortality compared with Redo-SAVR.


Introduction
Bioprosthetic valves are the most frequently used valve substitutes for surgical aortic valve replacement (SAVR). However, their long-term durability is limited by structural valve deterioration. 1 About one-third of bioprosthetic valves present signs of structural and hemodynamic deterioration at 10 years following SAVR, and 40% of the patients who survive up to 20 years after SAVR require an aortic valve reintervention for failed bioprosthetic valve. [1][2][3] Redo-SAVR remains the standard of care for the treatment of failed surgical bioprosthetic valves but is associated with a higher risk of periprocedural complications and in-hospital mortality compared with the first SAVR. In recent years, transcatheter aortic valve-in-valve implantation (ViV-TAVR) has become a valuable option for the treatment of failed surgical aortic bioprostheses (BPs) in patients with prohibitive or high risk for Redo-SAVR. [4][5][6][7] However, there are no randomized studies that have compared the prosthetic valve hemodynamic performance post-reintervention and the long-term clinical outcomes between patients who underwent ViV-TAVR vs. Redo-SAVR. Some reports suggest higher rates of high residual transvalvular gradients and severe prosthesis-patient mismatch following the procedure, but probable similar or better short-term clinical outcomes with ViV-TAVR vs. Redo-SAVR. 8,9 The objectives of this study were to compare hemodynamics using the new Valve Academic Research Consortium-3 (VARC-3) criteria and clinical outcomes of ViV-TAVR vs. Redo-SAVR at 30 days, at long-term follow-up, and to determine the factors associated with outcomes.

Study Population
In this observational single-center study, we retrospectively analyzed the data prospectively collected from 184 consecutive patients who underwent Redo-SAVR or ViV-TAVR for failed aortic surgical bioprosthetic valve due to structural valve deterioration between 2009 and 2017 at the Institut Universitaire de Cardiologie et de Pneumologie de Qu ebec. The period of inclusion was chosen so that the last patient included in the study theoretically had at least 3 years of follow-up. Patients with reintervention for valve thrombosis, endocarditis, or paravalvular regurgitation were excluded. Additional concomitant coronary revascularization (coronary artery bypass graft [CABG]), ascending aorta intervention, and mitral or tricuspid valve repair/replacement were not considered as exclusion criteria.
Pre-reintervention, reintervention, and post-reintervention clinical data were prospectively gathered in an institutional database. However, the present study was not a prespecified analysis at the time of the setup of the database, and this study should thus be considered retrospective in nature. Transthoracic echocardiograms obtained prior to and 1 to 3 months after reintervention were retrospectively analyzed in an echocardiography core laboratory according to the VARC-3 criteria. 10 The study was conducted in accordance with the Declaration of Helsinki, approved by the institutional review board, and because of its retrospective nature, informed written consent was not required.

Echocardiographic Data
All echocardiographic measurements were performed using the TOM-TEC Imaging platform (V.4.6, Image Arena TM, Munich, Germany) software. The mean transvalvular pressure gradient (MG), aortic valve area, and Doppler velocity index were measured with the Bernoulli equation and as recommended by guidelines. 11 The severity grades of aortic (AR), mitral, and tricuspid valve regurgitations were assessed using a multiparameter integrative approach as previously described. 11,12 The stroke volume was calculated by multiplying the cross-sectional area of the left ventricular outflow tract with the velocity-time integral measured below the prosthesis stent. 11 The effective orifice area (EOA) was calculated using the continuity Table 1 Baseline clinical characteristics of the total cohort and according to the type of reintervention Types of bioprosthetic valve dysfunction before reintervention were categorized as follows: (1) stenosis, if the mean gradient was !30 mm Hg without significant AR (!moderate); (2) regurgitation, if AR was greater than or equal to moderate without significant stenosis (gradient <30 mm Hg); or (3) mixed, if mean gradient was !30 mm Hg with greater than or equal to moderate AR.
Because transthoracic echocardiogram images were not available at the time of the first SAVR, pre-existing prosthesis-patient mismatch (PPM) after the first SAVR was assessed using the predicted indexed EOA (i.e., the normal reference value of EOA for the model and size of BP implanted in the patient divided by the patient's body surface area) as previously described. 11 PPM post-reintervention was assessed using the EOAi measured at predischarge echocardiogram. [13][14][15] PPM (preintervention and postintervention) was defined as not clinically significant (i.e., mild or no PPM) if the indexed EOA was >0.85 cm 2 /m 2 (or >0.70 cm 2 /m 2 if patients are obese: body mass index !30 kg/m 2 ), moderate if it was >0.65 cm 2 /m 2 but 0.85 cm 2 /m 2 (or >0.55 cm 2 /m 2 but 0.70 cm 2 /m 2 , if obese), and severe if it was 0.65 cm 2 /m 2 (or 0.55 cm 2 /m 2 if obese). Intended hemodynamic performance (IHP) of the valve was defined by mean gradient <20 mm Hg, peak velocity <3 m/s, Doppler velocity index !0.25, and less than moderate AR measured at predischarge echocardiogram. 10 Hemodynamic futility of reintervention was defined as a reduction in MG <10 mm Hg and no improvement in AR at predischarge echocardiogram vs. pre-reintervention echocardiogram.

Study Endpoints
The primary study endpoints were (1) device success as defined by VARC-3 10 : composite of technical success, freedom from mortality at 30 days, freedom from surgery or intervention related to the device at 30 days, and IHP; and (2) all-cause mortality.
Mortality data were retrospectively obtained from the Qu ebec Institute of Statistics. To maximize the interrogation of the central Qu ebec Institute of Statistics database, a list with multiple demographics (including first and last names, date of birth, and social security number) and a delay of 1 year between interrogation and closing follow-up dates were used.

Statistical Analyses
Continuous variables were tested for normality by the Shapiro-Wilk or the Kolmogorov-Smirnov tests and expressed as mean AE standard deviation (or as median and interquartile range if not normally distributed). For normal and nonparametric continuous distributions, a Student's t-test and a Mann-Whitney test were performed, respectively. Categorical variables were compared using the chi-squared or Fisher's exact tests, as appropriate, and are expressed in number of patients with percentages. Univariable and multivariable regression models were used to identify factors associated with (1) device success at 30 days, (2) IHP post-reintervention, (3) severe PPM post-reintervention, and (4) all-cause mortality. Multivariable logistic regression analyses were first performed to determine the factors associated with device success, IHP, severe PPM in the global population, and then respectively in the ViV-TAVR and Redo-SAVR population. Survival curves were constructed using time-to-event Kaplan-Meier curves, and a log-rank test was also conducted for comparison between groups. Univariable Cox proportional hazards models were used to identify the factors associated with all-cause mortality following reintervention, and the results are presented as hazard ratio (HR) with 95% CIs. Comprehensive multivariable Cox analyses were limited in the number of risk factors that could be included in a single model because of the sample size and small number of deaths from any cause during the follow-up. We thus built 4 different models of interest to test the independent association of ViV-TAVR vs. Redo-SAVR with the primary endpoint. The first model includes clinical baseline variables most strongly associated with univariate analysis (i.e., age, sex, chronic obstructive pulmonary disease, renal insufficiency, and EuroSCORE II). The second model includes the EuroSCORE II and pre-reintervention echocardiographic known relevant variables or those with univariable p value <0.10. The third model includes the EuroSCORE II and post-reintervention echocardiographic relevant variables or those with p value <0.10, which can impact the long-term outcome (i.e., stroke volume index post-reintervention 35 mL/m 2 , mitral regurgitation or tricuspid regurgitation greater than or equal to moderate, and IHP). The fourth model includes the same variables as the third model but with device success instead of IHP. A propensity score was calculated from logistic regression, including age, sex, EuroSCORE II, and each baseline characteristic that differs between the treated populations (p value <0.20; Supplemental Table 1). The inverse probability of treatment weighting (IPTW) technique was computed for each patient from the propensity score previously calculated. Then, a multivariable Cox model was performed to confirm the factors independently associated with all-cause mortality following Redo-SAVR and ViV-TAVR. All statistical analyses were performed using SPSS 26.0 (IBM Corporation, Armonk, New York, New York), and a p value <0.05 was considered as statistically significant.

Baseline Clinical and Echocardiographic Characteristics
Among the 184 patients who underwent reintervention for failed surgical aortic BPs, 104 (56.5%) underwent Redo-SAVR and 80 (43.5%) ViV-TAVR. Baseline characteristics of the study population according to the type of intervention are presented in Table 1.
Baseline echocardiographic data are presented in Table 2. The median time from the first SAVR to reintervention was 8.9 (5.8-12.9) years in the Redo-SAVR group compared with 10.8 (7.4-14.9) in the ViV-TAVR group (p < 0.001; Supplemental Table 2). However, echocardiographic data at the time of reintervention were not significantly different between groups ( Table 2). The proportion of stented vs. stentless surgical BPs was similar between groups, but patients who underwent ViV-TAVR had more frequently a surgical BP size 21 mm (32.5% vs. 12.5%, p ¼ 0.001) and pre-existing moderate or severe PPM (39.1% vs. 22.1%, p ¼ 0.02; Supplemental Table 2).

Procedural and In-Hospital Data
One-third of the patients underwent concomitant coronary revascularization (CABG or PCI) during reintervention, without a difference between groups (Supplemental Table 3). Seventy-five (72.1%) patients underwent a concomitant procedure on the aorta or the other valves during the Redo-SAVR, including aortic root enlargement or replacement in 22 (21.1%) patients, ascending aorta replacement in 25 (24.0%) patients, mitral valve repair or replacement in 22 (21.1%), and tricuspid valve repair in 6 (5.8%) (Supplemental Table 3). In patients who underwent ViV-TAVR, transfemoral access was used in 47 (58.8%) patients,  Table 3). Fracturing of the surgical bioprosthetic valve stent at the time of ViV-TAVR was not performed in any of the patients included in this series. Procedural and in-hospital complications are presented in Supplemental Table 4. The new onset of atrial fibrillation was more frequent in patients who underwent Redo-SAVR compared with those with ViV-TAVR (29 [28.2%] vs. 5 [6.8%], p < 0.001). The hospital stay duration (from admission to discharge) was longer for patients with Redo-SAVR vs. those with ViV-TAVR (9.7 AE 5.5 days vs. 6.8 AE 4.9 days; p < 0.001).
In the overall study population (ViV-TAVR þ Redo-SAVR), the factors associated with device success, IHP, and severe PPM following reintervention in univariate analysis are presented in Table 4 Table 4).
severe PPM and high residual gradients compared with Redo-SAVR, whereas the rates of moderate/severe AR and hemodynamic futility of reintervention were low and not significantly different between groups; (2) There was a trend toward lower 30-day and 1-year mortality with ViV-TAVR vs. Redo-SAVR; (3) Redo-SAVR is independently associated with better long-term survival compared with ViV-TAVR, confirmed by IPTW-adjusted analyses.
Early Hemodynamic Outcome of ViV-TAVR vs. Redo-SAVR The present study confirms and expands previous reports suggesting that Redo-SAVR has greater potential to improve valve EOA and thus decrease gradients, compared with ViV-TAVR in patients with failed bioprosthetic valve. 8,9,16 On the one hand, ViV-TAVR significantly improves aortic valve hemodynamics with a low and similar rate of hemodynamic futility compared with Redo-SAVR (7.8% vs. 7.0%). On the other hand, ViV-TAVR was associated with higher rates of severe PPM and high residual gradients, leading to superiority of Redo-SAVR over ViV-TAVR with regard to IHP (Redo-SAVR [67.7%] vs. ViV-TAVR [39.2%]; p < 0.001; OR [95% CI]: 3.25 [1.74-6.09]; p < 0.001) and device success (59.6% vs. 35.0%), despite a similar and low rate of moderate/severe AR in both groups.
The nature of both interventions, by definition, a new valve implanted within the failed surgical BP that is left in place in case of ViV-TAVR, compared with an explanation of the failed valve replaced by a new one in case of Redo-SAVR, explain the difference in hemodynamics postreintervention and also the risk of worse hemodynamics when ViV-TAVR is performed in stenotic (or mixed) failed bioprosthetic valve (compared with regurgitant valves). In comparison to the study recently published by Landes et al, 17 the present study reports a higher prevalence of high residual gradient (56.2% vs. 21.5%) and a smaller average EOA (1.11 cm 2 vs. 1.37 cm 2 ) in ViV-TAVR patients. These differences may be, at least in part, explained by the higher prevalence of patients who received a small ( 21 mm) surgical aortic valve BP at the time of the first aortic valve replacement (32.5% vs. 24.8%) and the much higher rate of use of balloon-expandable transcatheter valves for the ViV-TAVR (62.5% vs. 30.3%) in our study. To date, the clinical relevance and impact of severe PPM and high residual gradients following ViV-TAVR remain unclear, 14,[18][19][20] in the present study, there was no association between IHP, severe PPM, or high residual gradients at predischarge echocardiogram and 1-year or long-term outcomes. Furthermore, the overestimation of PPM and transprosthetic gradients by Doppler echocardiography, which  appears to be more common following ViV-TAVR vs. de novo TAVR or SAVR, 14,20 may play a role in these findings. Hence, both types of reinterventions achieve significant improvement in valve hemodynamics in the vast majority of patients with failed surgical BPs. Although device success was associated with better survival, this association did not remain statistically significant in multivariable analysis (Supplemental Tables 7 and 8).

Short-and Long-Term Clinical Outcomes of ViV-TAVR vs. Redo-SAVR
The lower risk of pacemaker implantation, new onset of atrial fibrillation, renal failure, stroke/TIA, shorter hospital stays, and lower inhospital and short-term mortality following ViV-TAVR vs. Redo-SAVR observed in the present study are consistent with the results of recent studies and meta-analyses. [4][5][6][7]9,16,21 These excellent short-term clinical outcomes of ViV-TAVR promote the adoption of this less invasive strategy for the treatment of failed bioprosthetic valves in patients with high surgical risk. 22,23 However, data at mid-and long-term are too conflicting to give a clear recommendation between ViV-TAVR and Redo-SAVR in patients at intermediate risk and low risk with longer expected life expectancy. Whereas Tam et al reported better 5-year survival rates in patients treated by ViV-TAVR vs. Redo-SAVR, 4 Deharo et al 5 found higher rates of heart failure, rehospitalization, and mortality beyond 1-year post-ViV-TAVR compared with Redo-SAVR. In the present study, a crossing of the mortality curves at approximately 3 years postprocedure was found, with lower mortality rates in ViV-TAVR vs. Redo-SAVR before 3 years and higher rates thereafter (Figure 4). Several factors may have contributed to this observation: first, nontransfemoral access was used in 41% of the ViV-TAVR patients included in the present series that was initiated in 2009 to have a long-term clinical follow-up. In randomized trials, transfemoral de novo TAVR is associated with similar or even better outcomes than SAVR, whereas transapical or other nontransfemoral TAVR access is known to be associated with worse outcomes, and these results are consistent with our findings.
Second, in the present investigation, as well as in several other previous studies, 24,25 the early valve hemodynamic factors were not associated with subsequent clinical outcomes.
Third, despite a similar rate of concomitant coronary revascularization procedures in ViV-TAVR vs. Redo-SAVR, the effectiveness of revascularization by CABG (compared with PCI) may have contributed to reduce ischemic events and mortality in the long-term follow-up. Moreover, although a more aggressive surgical strategy of concomitant mitral and/or tricuspid valve intervention is associated with higher short-term mortality, the reduction of the rate of mitral or tricuspid regurgitations greater than or equal to moderate in patients with Redo-SAVR may have brought a long-term benefit. Hence, the absence or incompleteness of concomitant procedures to treat pre-existing comorbidities at the time of ViV-TAVR may be one of the main factors leading to the excess mortality observed beyond 3 years in this group.

Clinical Implication and the Pivotal Role of the Heart Team
Based on the findings of the present study but also those previously reported, the role of the heart team and an individual case-by-case approach are strongly reinforced. The consideration of several factors by the heart team including surgical risk, pre-existing severe PPM, mode of surgical BP failure, type of bioprosthetic valve, comorbidities (such as complex coronary artery disease, and significant mitral or tricuspid valve regurgitation), and feasibility of transfemoral access; is key to selecting the most appropriate type of reintervention (Supplemental Figure 4).
ViV-TAVR should likely be considered in patients with (1) prohibitive or very high surgical risk; or (2) low, intermediate, or high surgical risk having none of the risk markers mentioned previously. To improve the long-term outcomes in patients referred for ViV-TAVR, concomitant or staged coronary and other concomitant valve procedures such as BP stent fracture should be considered in this population. Previous studies have reported that stent fracture improves hemodynamics and reduces the rate of severe PPM or high gradients. 26,27 Limitations Although the present study provides a first overview of the long-term comparison between ViV-TAVR and Redo-SAVR for structural bioprosthetic failure, uses for the first time the new VARC-3 criteria in this field of research, and adds valuable information compared with previous studies, several limitations should be noted. This is a retrospective and observational single-center study, which may have introduced biases including treatment allocation bias. Moreover, to obtain a long-term follow-up, this study was conducted over a large period of screening (2009-2017). The study was designed to reflect the real practice during the last decade, but the nonrandomized design may also have induced some biases regarding the evolution of clinical practice (several generations of THV, high prevalence of transapical implantation in the early experience, etc.). In the future, the increasing use of minimally invasive access such as transfemoral and carotid access may contribute to improve short-and long-term clinical outcomes of ViV-TAVR.
There were several differences in the baseline characteristics between the 2 treatment groups including longer from first aortic valve replacement to surgical BP failure and higher frequency of small surgical BPs and of pre-existing PPM. We attempted to adjust for these differences using IPTW, but we cannot exclude that some unmeasured confounding factors may be present and different between ViV-TAVR vs. Redo-SAVR.

Conclusions
On the one hand, ViV-TAVR was associated with a lower rate of IHP, which was essentially driven by higher rate of high residual gradients compared with Redo-SAVR. On the other hand, the rates of moderate/ severe AR and of hemodynamic futility of reintervention were low and not significantly different between groups. Although there was a trend for lower 30-day and 1-year mortality with ViV-TAVR vs. Redo-SAVR, the latter was associated with better long-term survival compared with ViV-TAVR. These results emphasized that the choice between ViV-TAVR and Redo-SAVR should be individualized depending on the clinical and anatomical characteristics and comorbidities of each patient. funded, in part, by a research grant from (grant # FDN-143225; Ottawa, Ontario, Canada).

Supplementary Material
Supplemental data for this article can be accessed on the publisher's website.